Hematopoiesis is an essential, lifelong process whereby highly specialized blood cells are generated from hematopoietic stem cells, including cells responsible for carbon dioxide and oxygen transport (erythrocytes), blood clotting (platelets), humoral immunity (B lymphocytes), cellular immunity (T lymphocytes), as well as cells which respond to foreign organisms and their products (granulocytes, monocytes, and macrophages).
Mature functional end cells and their immediate precursors have a limited life-span and a limited proliferative capacity and hence are not self-maintaining. Thus, these cells are continuously replaced from a pool of more primitive proliferating progenitor cells. The proliferation and self-renewal of these cells depend on stem cell factor (SCF). Glycoprotein growth factors regulate the proliferation and maturation of the cells that enter the blood from the marrow, and cause cells in one or more committed cell lines to proliferate and mature. Three more factors which stimulate the production of committed stem cells are called colony-stimulating factors (CSFs) and include granulocyte-macrophage CSF (GM-CSF), granulocyte CSF (G-CSF) and macrophage CSF (M-CSF).
Under normal conditions, senescent mature cells are continuously removed and replaced with newly generated cells. Under stress conditions, there may be an increased rate at which blood cells are destroyed or lost, or there may be a compromised capacity to replenish cells undergoing normal senescent attrition, resulting in depletion of erythrocytes (anemia), platelets (thrombocytopenia), leukocytes (leukopenia) including neutrophil granulocytes (neutropenia), and/or agranulocytosis (complete absence of white cells).
Radiation and chemotherapeutic treatment frequently produce severe reversible neutropenia or agranulocytosis, thrombocytopenia, and anemia. This effect comes about as the result of the toxicity of these treatment regimens on dividing hematopoietic stem cells and the consequent depletion of hematopoietic precursors and of the cells responsible for producing the required CSFs and hematopoietic potentiators. The depletion of hematopoietic precursors in the bone marrow associated with chemotherapy and irradiation sometimes results in life-threatening hemorrhagic and infectious complications. Severe suppression of hematopoiesis is a major factor in limiting chemotherapy use and dose escalation. Replacement of depleted blood cell types by transfusion is not always practical or desirable as it often affords only temporary improvement, is expensive, and is associated with risks of infection, fluid overload, and immune-mediated adverse reactions. Thus there has been intense interest in developing methods of using hematopoietic CSFs and potentiators to treat neutropenia, agranulocytosis, thrombocytopenia, and anemia.
In recent years three recombinant human hematopoietic growth factors became available for clinical use: erythropoietin (EPO) for stimulating the production of erythrocytes in the treatment of anemia, as well as G-CSF and GM-CSF for stimulating the production of neutrophils in the treatment of neutropenia. Apart from their effect on stimulating granulopoiesis, G-CSF and GM-CSF also mobilize large numbers of hematopoietic stem and progenitor cells (HSPCs) from the bone marrow into the peripheral blood, which further accelerates reconstitution of the hematopoietic system. HSPC mobilization is mediated by several factors including trans-acting signals that originate from the release of proteases including serine- and metallo-proteinases whose substrates include various molecules implicated in progenitor trafficking such as VCAM-1 membrane-bound Kit ligand, the c-Kit receptor, stromal-derived factor-1 (SDF-1 or CXCL12) and its cognate receptor CXCR4.
In work leading up to the present invention, it was discovered that E-selectin, a Ca2+-dependent adhesion molecule expressed by bone marrow endothelial sinuses and on inflamed endothelial cells, regulates hematopoietic stem cell turn-over in the bone marrow. In particular, the present inventors determined that the absence of E-selectin at the endothelial niche significantly delays hematopoietic stem cell turnover and that blocking E-selectin mediated adhesive interactions protects hematopoietic stem cells from medical treatments that target rapidly dividing cells, including myeloablative therapies such as radiation and chemotherapeutic treatments. Accordingly, it was proposed that E-selectin antagonists would be useful for treating or preventing immunocompromised conditions such as neutropenia, agranulocytosis, thrombocytopenia, and anemia, which result from medical treatment.